HK1182315B - Stable ready to use injectable paracetamol formulation - Google Patents

Description

Stable ready-to-use paracetamol injection formulations

The present invention relates to a pharmaceutical composition for parenteral administration by intravenous drip comprising paracetamol, which composition has an optimal pH value of 6.0 (in the range between 5.5 and 6.5); the composition contains, in appropriate concentrations: at least one acetaminophen dissolution stabilizing compound selected from the group consisting of cyclodextrins, at least one stabilizing compound having at least one mercapto functional group, and at least one stabilizing compound selected from the group consisting of vitamin B1(Thiamine) salts; the composition is capable of stabilizing acetaminophen and increasing its solubility even at high temperatures.

Technical Field

The present invention relates to an acetaminophen injection composition as set forth in claim 1, which is stable even after storage at high temperature for a long period of time.

Background

Acetaminophen is generally considered to be the major active metabolite of phenacetin and acetanilide having analgesic and antipyretic properties. Acetaminophen has analgesic and antipyretic effects comparable to aspirin but exhibits weak anti-inflammatory effects, and thus has limited use in inflammatory rheumatic diseases.

A large number of pharmaceutical preparations for oral or even topical administration are known. However, since acetaminophen is very insoluble in water and its solution dissolved in an aqueous medium is unstable because it is decomposed in the presence of oxygen and/or light through multiple degradation pathways, it is difficult to obtain a pharmaceutical preparation for injection, particularly a ready-to-use solution for intravenous drip; this is well known and described, for example, in "stability of N-acetyl to aminophenol aqueous solution" published by K.T.Koshy and J.L.Lach in "journal of pharmaceutical sciences (J.of pharmaceutical Science)," Vol.50 (phase 2) (1961, month 2) "page 113-. The presence of degradation species that lead to solution coloration suggests this instability of acetaminophen in aqueous media. Various substances that cause staining of solutions include the benzimidazolones, which are hepatotoxic in humans.

However, coloration in pharmaceutical solutions (especially in injectable formulations which must be completely transparent) is a serious problem, since the presence of this color indicates the presence of harmful compounds in the formulation, thus leading to rejection of the injected drug without being used.

One reason for acetaminophen degradation is based on chemical oxidation reactions, where oxygen present in the solution is the major factor in the degradation. The second cause of degradation may be deacetylation of p-aminophenol generating an amino group, which is also rapidly degraded to generate p-benzoquinone imide. This deacetylation reaction can occur at both acidic and basic pH values (much faster) once the phenolate form is present.

A stable acetaminophen solution dissolved in an aqueous medium can be obtained by several related operations.

(1) An optimum pH value was established to prevent or minimize 4-aminophenol formation, as indicated by k.thomas Koshy and Jon l.lach in the aforementioned reference article "stability of N-acetyl to an aqueous solution of aminophenol" at phase 2 (1961) vol 50, page 113-118, of j.of phar.sci. to minimize hydrolysis of the acetyl group of acetaminophen between pH =4.5 and pH = 6.0.

(2) Preventing the presence of oxygen in the solution. This operation is described in spanish patent No. 2,201,316 to Pharmatop SCR and verified in spanish european patent EP 858,329B 1. This patent document discloses a method: the main factor (oxygen) causing the reaction was excluded by bubbling nitrogen gas, thereby preventing oxidation of acetaminophen. The solution was then stored in a fully sealed bottle, thereby ensuring stability of acetaminophen in the solution over time and minimizing impurity levels and rendering the solution completely colorless. It is believed that this product of the prior art must be stored in suitable bottles that prevent oxygen from penetrating into the solution, and therefore these solutions cannot be stored in separate oxygen permeable bottles (e.g. plastic material).

In addition, U.S. patent 6,028,222 discloses analgesic formulations that utilize free radical antagonists or scavengers (which may be polyols or organic compounds substituted with one or more mercapto functional groups) to provide stable acetaminophen. Us patent 4,727,064 discloses the use of alkylated cyclodextrins to increase the solubility of drugs, particularly acetaminophen, in water.

Despite the prior art achievements, due to the increasing demands on quality and safety, there is a continuing need to further improve the stability of aqueous paracetamol solutions for intravenous drip, even after a long period of time at high temperatures and without the need to keep the solution in a completely sealed bottle.

Disclosure of Invention

Accordingly, the present invention relates to a stable aqueous paracetamol solution for intravenous drip; the aqueous solution contains: at least one acetaminophen dissolution stabilizing compound selected from the group consisting of cyclodextrins, at least one stabilizing compound having at least one mercapto functional group, and at least one stabilizing compound selected from the group consisting of vitamin B1 salts.

The total concentration of at least one paracetamol dissolution stabilizing compound selected from the group consisting of cyclodextrins, at least one stabilizing compound having at least one thiol functional group, and at least one stabilizing compound selected from the group consisting of vitamin B1 salts in the solution is preferably between 0.001% and 20% m/v.

The aqueous paracetamol solution according to the invention may have a pH between 4.0 and 7.0. Generally, the solution may be a buffer prepared with a buffer composition selected from at least one of acid forms and ionized forms of citric acid, malic acid, acetic acid, sorbic acid, phosphoric acid, fumaric acid, lactic acid, gluconic acid, and tartaric acid, or mixtures thereof. Preferably, the pH is between 5.5 and 6.5, more preferably the pH is adjusted to 6. One typical buffer includes: phosphate or sodium citrate/acetate, preferably disodium phosphate dihydrate.

Preferred cyclodextrins are hydroxyalkyl-cyclodextrins, especially 2-hydroxypropyl-beta-cyclodextrin. Typically, the concentration of the at least one paracetamol selected from the group consisting of cyclodextrins in the solution is between 0.2% m/v and 19% m/v, preferably between 0.2% m/v and 6.0% m/v, more preferably between 0.5% and 3.0% m/v.

Preferably, the 2-hydroxypropyl-beta-cyclodextrin (HPBCD) is selected from derivatives having a degree of hydroxypropyl substitution per beta-cyclodextrin molecule preferably between 2.5 and 10, more preferably between 3.5 and 8. The molar ratio of paracetamol to 2-hydroxypropyl-beta-cyclodextrin is preferably from 100:1 to 0.1:1, more preferably 5:1, most preferably 1.5: 1.

The at least one stabilizing compound having at least one mercapto-functional group is selected from: thioglycerides, cysteine, acetylcysteine, thioglycolic acid and/or salts thereof, dithiothreitol, reduced glutathione, thiolactic acid and/or salts thereof, thiourea and 2-mercaptoethane sulfonic acid, typically thioglycerol, preferably monothioglycerol, the concentration of the stabilizing compound being between 0.001% m/v and 0.2% m/v.

At least one stabilizing compound selected from the group consisting of vitamin B1 salts, preferably vitamin B1 hydrochloride, is preferably present at a concentration of between 0.001% m/v and 0.2% m/v.

In addition, the aqueous solution of the present invention may further contain other chelating or complexing agents. The chelating or complexing agent in solution may be selected from: EDTA, nitrilotriacetic acid (nitrilotriacetic acid), ethylenediamine-N, N '-diacetic acid-N, N' -dipropionic acid, ethylenediamine-tetrakis (methylenephosphoric acid), 2'- (ethylenediamine) -dibutanoic acid, ethylene glycol di (2-aminoethyl ether) -N, N' -tetraacetic acid, and/or salts thereof, preferably EDTA. Preferably, the concentration of the chelating or complexing agent is between 0.001% m/v and 0.2% m/v.

The stable aqueous paracetamol solution according to the invention may further comprise an isotonic agent, preferably sodium chloride.

The stable aqueous paracetamol solution for intravenous drip may be sterilized by heating or filtration.

Typical concentrations of paracetamol are between 0.20% and 10% m/v, preferably between 0.5% and 1.5% m/v.

Can utilize water insoluble inert gas (N)₂) The aqueous medium of the solution according to the invention is deoxygenated.

The composition according to the invention will be administered intravenously and will be stable if stored for more than 24 months at room temperature. Moreover, the composition is stable even after storage at elevated temperatures (e.g., 70 ℃) for greater than 30 days.

The composition can be prepared as a solution and stored in a clean glass container or bottle made of a polymeric material (e.g., polyethylene) or in a soft material bag made of polyethylene, polyvinyl chloride, or polypropylene.

The molar ratio of paracetamol to cyclodextrin is preferably from 100:1 to 0.1:1, more preferably 5:1, most preferably 1.5: 1.

Typically, the solution contains 2mg to 200mg, preferably greater than 5mg, most preferably 10mg, of acetaminophen per ml of solution.

The solution may contain from 0.001 to 5mg, preferably from 0.0015 to 1mg, most preferably 0.1mg, of complexing or chelating agent per ml.

Furthermore, the solution typically contains 2mg to 150mg, preferably more than 3mg, most preferably between 6mg and 7mg of cyclodextrin per ml.

The solution may contain 0.01 to 5mg, preferably 0.015 to 1mg, most preferably 0.1mg per ml of at least one stabilizing compound (preferably monothioglycerol) having at least one thiol functional group.

The solution may contain 0.01 to 5mg, preferably 0.015 to 1mg, most preferably 0.1mg per ml of at least one stabilizing compound selected from the group consisting of vitamin B1 salts (preferably vitamin B1 hydrochloride).

Advantageously, the solution is in the form of a unit dose of not more than 100 ml.

Detailed Description

The present inventors have found a process for preparing a stable aqueous solution comprising at appropriate concentrations in solution at least one paracetamol selected from the group consisting of cyclodextrins, at least one stabilizing compound having at least one thiol functional group, and at least one stabilizing compound selected from the group consisting of vitamin B1 salts; the aqueous solution is not only capable of having a concentration of acetaminophen greater than 10mg/ml solution, but is also stable and does not require refrigeration when packaged in a clean glass-sealed vial, or stoppered glass vial, or a bottle made from a polymeric material such as polyethylene, or a soft material bag made from polyethylene or polyvinyl chloride or polypropylene. By "stable" is meant that the solution can be stored at room temperature for at least 24 months and at elevated temperature (70 ℃) for at least 30 days, and does not develop coloration and particulate matter visible to the eye.

It has been found that the use of a dissolution stabilizing compound and a stabilizing compound, preferably a chelating agent, according to the present invention not only increases the solubility of acetaminophen to an extent that 1000mg of acetaminophen can be dissolved in 100ml of final volume, but also effectively stabilizes the solution to prevent the formation of particulates and color when the solution is stored in ampoules, vials and bags and at elevated temperatures.

The solution may be formulated in unit dosage forms, each unit dosage containing from 100mg to 1500mg, more preferably from 600mg to 1000mg, most preferably 1000mg of paracetamol, the volume of the unit dosage form not exceeding 100 ml.

The stabilized injectable solutions of the present invention can be prepared by methods known in the art.

The stabilized injection solutions of the present invention may be packaged in suitable containers known in the art (e.g., glass ampoules, glass vials, cartridges, glass-sealed glass vials, or stoppered glass vials, or bottles made from a polymeric material such as polyethylene, or bags made from polyethylene, polyvinyl chloride, or polypropylene). Preferably, the glass should be clear glass.

The stabilized injectable solutions of the present invention are suitable for intravenous administration.

The stabilized injectable solutions of the present invention provide a shelf life of at least 24 months without storage under refrigerated conditions, thereby saving refrigeration costs during transportation and storage, and alleviating patient discomfort during administration.

The invention will now be illustrated in more detail with reference to the following non-limiting examples.

Examples

Example 1

Preferred pharmaceutical compositions according to the invention contain:

table 1:

composition (I)	Amount/100 ml
		Acetaminophen	1000mg
Hydroxypropyl-beta-cyclodextrin (HPBCD)	666mg
		Monothioglycerol (MTG)	10mg
EDTA	10mg
		Vitamin B1 hydrochloride	10mg
NaCl	600mg
		Disodium phosphate dihydrate	35.6mg
Adding water for injection to	100ml
		Final pH (adjusted with 1M HCl or NaOH)	5.5-6.5

Example 2

The unit compositions of the second formulation (control, comparative) are provided in table 2 below:

table 2:

composition (I)	Amount/100 ml
		Acetaminophen	1000mg
Hydroxypropyl-beta-cyclodextrin (HPBCD)	666mg
		Monothioglycerol (MTG)	10mg
EDTA	10mg
		NaCl	600mg

Disodium phosphate dihydrate	35.6mg
		Adding water for injection to	100ml
Final pH (adjusted with 1M HCl or NaOH)	5.5-6.5

Example 3

The laboratory scale formulations given in examples 1 and 2 of the present invention were manufactured, filled into clean glass vials and polymeric materials (soft material bags) and stability studies were performed. The results obtained are summarized in tables 3 to 4 below:

table 3:

table 4:

the solution according to example 1 was still clean and colorless (in clean glass vials and soft material bags) after 40 days of storage at 70 ℃, with no visible particulates.

Stability evaluations in tables 3-4 indicate: the 1000mg/100ml paracetamol formulations and solutions according to the invention have advantages over control solutions with different compositions of the stabilizing compound.

Example 4

To prepare a 1000mg/100ml paracetamol unit formulation for intravenous injection, 8000ml water for injection (WFI) was purged with nitrogen to reduce oxygen. The water was heated to 50 ℃. The treatment was continued under a nitrogen blanket. 66.675g of HPBCD (DS 4.69) was added to the 60% WFI batch volume and stirred until dissolved. The solution was then allowed to cool to room temperature. The solution was prefiltered with a 0.45Pg filter, followed by the addition of 1g MTG, 1g EDTA, 60g NaCl, 1g vitamin B1 hydrochloride, and 3.56g disodium phosphate dihydrate. The solution was stirred until all of the MTG, EDTA, NaCl, vitamin B1 hydrochloride, and disodium phosphate dihydrate were dissolved. The pH was then adjusted to 6 with 1M HCl. 100g of acetaminophen was added to the solution and stirred until dissolved. The pH was adjusted to 6 (as required) and adjusted to 100% by volume with WFI. The 1000mg/100ml paracetamol solution formed was sterilized by filtration using a 0.22Pm filter and filled into pre-sterilized glass vials or bags under sterile conditions. The glass vial or bag is sealed under sterile conditions under nitrogen. The formulation contained 1000mg/100ml paracetamol as confirmed by HPLC.

Claims (9)

1. A stable aqueous paracetamol solution for intravenous drip comprising: at least one paracetamol dissolution stabilizing compound selected from the group consisting of cyclodextrins, at least one stabilizing compound having at least one thiol functional group, and at least one stabilizing compound selected from the group consisting of vitamin B1 salts, wherein the concentration of the at least one stabilizing compound selected from the group consisting of vitamin B1 salts is between 0.001% m/v and 0.2% m/v.

2. The stable aqueous solution of claim 1, wherein the at least one acetaminophen dissolution stabilizing compound in solution is selected from the group consisting of hydroxyalkyl- β -cyclodextrins.

3. The stable aqueous paracetamol solution according to claim 1 or 2, wherein the at least one dissolution stabilizing compound of paracetamol in solution is 2-hydroxypropyl- β -cyclodextrin.

4. A stable aqueous solution according to any one of claims 1 to 3, wherein the concentration of the at least one paracetamol in solution at the dissolution stabilizing compound is between 0.5% m/v and 3.0% m/v.

5. The stable aqueous paracetamol solution according to any one of the preceding claims, further comprising a chelating agent.

6. The stable aqueous paracetamol solution according to claim 5, wherein the chelating agent is selected from the group consisting of: EDTA, nitrilotriacetic acid, ethylenediamine-N, N '-diacetic acid-N, N' -dipropionic acid, ethylenediamine-tetrakis (methylenephosphoric acid), 2'- (ethylenediamine) -dibutanoic acid, ethylene glycol bis (2-aminoethyl ether) -N, N' -tetraacetic acid, and/or salts thereof.

7. The stable aqueous paracetamol solution according to claim 5 or 6, wherein the concentration of the chelating agent is between 0.001% m/v and 0.2% m/v.

8. The stable aqueous paracetamol solution according to any one of the preceding claims, wherein the pH-value is between 4.0 and 7, the solution being buffered with a buffer composition selected from at least one of the acid and ionized forms of citric, malic, acetic, sorbic, phosphoric, fumaric, lactic, gluconic and tartaric acids or mixtures thereof.

9. The stable aqueous paracetamol solution according to any one of the preceding claims, wherein the concentration of paracetamol is between 0.5% and 1.5% m/v.